Crohn s disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory bowel diseases (IBD) that have a combined prevalence of ~100-200 per 100,000 in developed countries. Epidemiological studies reveal a significant genetic contribution to the pathogenesis of IBD, with a relative risk to siblings of affected individuals (lambda's) estimated at 30-40 fold for CD and 10-20 fold for UC. Both diseases involve altered expression of proinflammatory and immunoregulatory cytokines within the intestinal mucosa. Prior studies in our laboratory implicated a locus in the cytokine gene cluster on chromosome 5q31, and we have performed the first extensive high resolution single nucleotide polymorphism (SNP) analysis of the human genome within this region. In addition to the discovery of a novel CD risk factor, we described for the first time the striking haplotype structure of the human genome. Understanding this haplotype structure enabled us to proceed from an 18 cM linkage peak to a 250 kb segment in which a common haplotype (present in greater than 75% of CD patients) was conclusively shown to confer significant risk. Knowledge of this structure of genetic variation forms the underpinnings of the current proposal. Several groups, including our own, have identified two other regions with arguably the strongest linkage evidence to date for IBD, chromosome 19p13 and 6p21. In the current proposal we aim to define the haplotype structure on chromosomes 6 and 19 and to identify the causal genetic variation conferring susceptibility to IBID. This project has two primary aims. First we will assemble a large, carefully phenotyped collection of over 1000 IBD patients from the Province of Quebec, a region with known founder populations. The collection will be performed together with the Quebec IBD Genetics Consortium (QIGC). Secondly we will perform comprehensive analysis of genetic variation using genetic approaches enabled by the complete human genome sequence an new understanding of genetic variation. The combination of a massive clinical consortium with state-of-the-art approaches to studying genetic variation represents the best hope for deciphering these complex genetic diseases.